Search

Thomas El Jammal,1 Yvan Jamilloux,1 Mathieu Gerfaud-Valentin,1 Dominique Valeyre,2 Pascal Sève1,3 1Department of Internal Medicine, Lyon University Hospital, Lyon, France; 2Department of Pneumology, Assistance Publique - Hôpitaux de Paris, Hôpital Avicenne et Université Paris 13, Sorbonne Paris Cité, Bobigny, France; 3Hospices Civils de Lyon, Pôle IMER, Lyon, F-69003, France, University Claude Bernard Lyon 1, HESPER EA 7425, Lyon F-69008, FranceCorrespondence: Pascal SèveService de Médecine Interne, Groupement Hospitalier Nord, 103 Grande rue de la Croix-Rousse, Lyon F-69004, FranceTel +33 426 732 636Fax +33 426 732 637Email pascal.seve@chu-lyon.frAbstract: Sarcoidosis is a multi-system disease of unknown etiology characterized by granuloma formation in various organs (especially lung and mediastinohilar lymph nodes). In more than half of patients, the disease resolves spontaneously. When indicated, it usually responds to corticosteroids, the first-line treatment, but some patients may not respond or tolerate them. An absence of treatment response is rare and urges for verifying the absence of a diagnosis error, the good adherence of the treatment, the presence of active lesions susceptible to respond since fibrotic lesions are irreversible. That is when second-line treatments, immunosuppressants (methotrexate, leflunomide, azathioprine, mycophenolate mofetil, hydroxychloroquine), should be considered. Methotrexate is the only first-line immunosuppressant validated by a randomized controlled trial. Refractory sarcoidosis is not yet a well-defined condition, but it remains a real challenge for the physicians. Herein, we considered refractory sarcoidosis as a disease in which second-line treatments are not sufficient to achieve satisfying disease control or satisfying corticosteroids tapering. Tumor necrosis alpha inhibitors, third-line treatments, have been validated through randomized controlled trials. There are currently no guidelines or recommendations regarding refractory sarcoidosis. Moreover, criteria defining non-response to treatment need to be clearly specified. The delay to achieve response to organ involvement and drugs also should be defined. In the past ten years, the efficacy of several immunosuppressants beforehand used in other autoimmune or inflammatory diseases was reported in refractory cases series. Among them, anti-CD20 antibodies (rituximab), repository corticotrophin injection, and anti-JAK therapy anti-interleukin-6 receptor monoclonal antibody (tocilizumab) were the main reported. Unfortunately, no clinical trial is available to validate their use in the case of sarcoidosis. Currently, other immunosuppressants such as JAK inhibitors are on trial to assess their efficacy in sarcoidosis. In this review, we propose to summarize the state of the art regarding the use of immunosuppressants and their management in the case of refractory or multidrug-resistant sarcoidosis.Keywords: refractory sarcoidosis, JAK inhibitors, anti-TNF

Yvan Jamilloux,1–3,* Mathieu Gerfaud-Valentin,1,* Thomas Henry,3 Pascal Sève1 1Department of Internal Medicine, Hôpital de la Croix-Rousse, Université Claude Bernard-Lyon 1, Lyon, France; 2Department of Biochemistry, University of Lausanne, Epalinges, Switzerland; 3International Research Center on Infectiology. INSERM U1111. Université Claude Bernard-Lyon 1, Lyon, France *These authors contributed equally to this work Abstract: Adult-onset Still’s disease (AOSD) is a rare inflammatory disorder that has been recently classified as a polygenic autoinflammatory disorder. The former classification, based on the disease course, seems to be quite dated. Indeed, there is accumulating evidence that AOSD can be divided into two distinct phenotypes based on cytokine profile, clinical presentation, and outcome, ie, a “systemic” pattern and an “articular” pattern. The first part of this review deals with the treatments that are currently available for AOSD. We then present the different strategies based on the characteristics of the disease according to clinical presentation. To do so, we focus on the two subsets of the disease. Finally, we discuss the management of life-threatening complications of AOSD, along with the therapeutic options during pregnancy. Keywords: adult-onset Still’s disease, treatment, anakinra, tocilizumab, canakinumab

To assess the diagnostic value of brain magnetic resonance imaging (bMRI) for the etiological diagnosis of uveitis and to establish predictive factors associated with its advantageous use. Retrospective study on all patients with de novo uveitis who were referred to our tertiary hospital and who underwent a bMRI between 2003 and 2018. bMRI was contributive in 19 out of 402 cases (5%), among patients with a contributive bMRI, 68% had neurological signs. Univariate analysis established that neurological signs (p <.001), granulomatous uveitis (p =.003), retinal vasculitis (p =.002), and intermediate uveitis (p <.001) were all significantly associated with a contributive bMRI. Multivariate analysis confirms the significant association of neurological signs (p <.001) and intermediate uveitis (p =.01). bMRI appears to be a relevant exam in specific cases; intermediate/posterior uveitis or panuveitis accompanied by neurological signs, retinal vasculitis, or in patients older than 40, to rule out an oculocerebral lymphoma. ACE: Angiotensin-Converting Enzyme; bMRI: Magnetic Resonance Imaging; CBC: Complete Blood cell Count; BMRI: Brain Magnetic Resonance Imaging; CT: Computerized Tomography; MS: Multiple Sclerosis; NS: Neurological Signs; OCL: Oculocerebral Lymphoma; RIS: Radiologically Isolated Syndrome [ABSTRACT FROM AUTHOR]

La sarcoïdose peut évoluer vers une maladie chronique dans environ 30 % des cas. Lorsqu'un traitement général est indiqué, les corticoïdes constituent le traitement de première ligne. Plus d'un tiers des patients traités par corticoïdes reçoivent un agent d'épargne cortisonique. Bien que le méthotrexate soit l'agent d'épargne le plus souvent employé, les antipaludéens de synthèse sont utilisés depuis plus de cinquante ans sur la base d'essais thérapeutiques, randomisés, de faible taille. Malgré ce faible niveau de preuve, la chloroquine ou plus souvent désormais l'hydroxychloroquine sont utilisées en pratique quotidienne, notamment pour traiter les sarcoïdoses cutanée et articulaire, ainsi que l'hypercalcémie et certaines uvéites. Cette revue synthétise l'état des connaissances sur le traitement d'épargne cortisonique dans la sarcoïdose, notamment dans sa forme extra-pulmonaire. Ces données étayent la nécessité de conduire des essais thérapeutiques de bonne qualité pour valider l'utilisation de l'hydroxychloroquine dans cette indication spécifique. Sarcoidosis can develop into a chronic disease in about 30% of cases. When general treatment is indicated, corticosteroids are the first-line treatment. More than one third of patients treated with corticosteroids receive a steroid-sparing agent. Although methotrexate is the most commonly used sparing agent, synthetic antimalarials have been used for more than fifty years on the basis of small, randomised, therapeutic trials. Despite this low level of evidence, chloroquine or more often hydroxychloroquine are used in daily practice, particularly to treat skin, bone and joint sarcoidosis, as well as hypercalcemia and certain types of uveitis. This review summarises the state of knowledge on steroid-sparing therapy in sarcoidosis, particularly in its extra-pulmonary form. These data support the need for good quality therapeutic trials to validate the use of hydroxychloroquine in this specific indication. [ABSTRACT FROM AUTHOR]

Summary: Background: A new autoinflammatory syndrome related to somatic mutations of UBA1 was recently described and called VEXAS syndrome ('Vacuoles, E1 Enzyme, X‐linked, Autoinflammatory, Somatic syndrome'). Objectives: To describe clinical characteristics, laboratory findings and outcomes of VEXAS syndrome. Methods: One hundred and sixteen patients with VEXAS syndrome were referred to a French multicentre registry between November 2020 and May 2021. The frequency and median of parameters and vital status, from diagnosis to the end of the follow‐up, were recorded. Results: The main clinical features of VEXAS syndrome were found to be skin lesions (83%), noninfectious fever (64%), weight loss (62%), lung involvement (50%), ocular symptoms (39%), relapsing chondritis (36%), venous thrombosis (35%), lymph nodes (34%) and arthralgia (27%). Haematological disease was present in 58 cases (50%): myelodysplastic syndrome (MDS; n = 58) and monoclonal gammopathy of unknown significance (n = 12; all patients with MGUS also have a MDS). UBA1 mutations included p.M41T (45%), p.M41V (30%), p.M41L (18%) and splice mutations (7%). After a median follow‐up of 3 years, 18 patients died (15·5%; nine of infection and three due to MDS progression). Unsupervised analysis identified three clusters: cluster 1 (47%; mild‐to‐moderate disease); cluster 2 (16%; underlying MDS and higher mortality rates); and cluster 3 (37%; constitutional manifestations, higher C‐reactive protein levels and less frequent chondritis). The 5‐year probability of survival was 84·2% in cluster 1, 50·5% in cluster 2 and 89·6% in cluster 3. The UBA1 p.Met41Leu mutation was associated with a better prognosis. Conclusions: VEXAS syndrome has a large spectrum of organ manifestations and shows different clinical and prognostic profiles. It also raises a potential impact of the identified UBA1 mutation. Whatis already known about this topic? VEXAS syndrome is a recently described autoinflammatory disease related to UBA1 mutation. The clinical phenotype includes patients with thrombosis, fever, chondritis, neutrophilic dermatosis and MDS. What does this study add? The main clinical features of VEXAS patients remain recurrent fever (64.7% vs. 72%, in original description by Beck et al.), skin lesions (83.6% vs. 88%), lung infiltrates (49.1% vs. 72%), unprovoked thrombosis (35.5% vs. 44%), with new features such as arthralgia (28.4%), ocular involvement (40.5%) or lymph node enlargement (34.5%), expanding the previous clinical phenotype of VEXAS syndrome.We identified 3 clusters of VEXAS syndrome, including an MDS‐related phenotype; mild‐to‐moderate disease with less fever, chondritis and thromboembolism, and one with more 'inflammatory' profile characterized by cutaneous vasculitis lesions and relapsing profile.A phenotype–genotype association was observed for UBA1 p.Met41Leu which was associated with less 'inflammatory' and mild‐to‐moderate phenotype and better overall prognosis. Linked Comment: L.T. Nicholson and L.M. Madigan. Br J Dermatol 2022; 186:392–393. Plain language summary available online [ABSTRACT FROM AUTHOR]

Background Studies on sarcoidosis in elderly patients are scarce and none have specifically evaluated patients aged ≥75 at onset. Aim We aimed to analyse the characteristics of patients with sarcoidosis diagnosed after 75 and to compare them with those of younger patients. Design Multicenter case–control study comparing elderly-onset sarcoidosis (EOS) with young-onset sarcoidosis (YOS) seen at Lyon University Hospitals between 2006 and 2018. Methods Using our institutional database, we included 34 patients in the EOS group and compared them with 102 controls from the YOS group in a 1:3 ratio. Demographic characteristics, medical history, clinical presentation, laboratory and imaging findings, sites of biopsies, histological analyses, treatments and outcomes were recorded using a comprehensive questionnaire. Results There were more Caucasians in the EOS group (94.1% vs. 59.8%; P  < 0.001), who had significantly more comorbidities (mean, 3.1 ± 2 vs. 1.1 ± 1.6; P  < 0.001). In the EOS group, there was less pulmonary involvement (26.5% vs. 49%; P  = 0.022), less lymphadenopathy (2.9% vs. 16.7%; P  = 0.041), no erythema nodosum (0% vs. 12.8%; P  = 0.029) and no arthralgia (0% vs. 25.5%; P  = 0.001). Conversely, uveitis was more common in the EOS group (55.9% vs. 20.6%; P  < 0.001). Pathological confirmation was obtained significantly less frequently in the EOS group (67.7% vs. 85.3%; P  = 0.023). Corticosteroid-related side effects were significantly more common in the EOS group (100% vs. 75.9%; P  = 0.030). Conclusion Epidemiology and clinical presentation of EOS differs from YOS, including more comorbidities and more uveitis. Elderly patients are more prone to corticosteroid side effects. [ABSTRACT FROM AUTHOR]